This is a revision of a competitive renewal application for a NIH RO1 grant entitled "Structures and Interactions of Chemokine Receptors" that has been funded during the past almost 10 years. The long standing interest and goals in this project are to understand the structure-function relationship and mechanism of chemokines and their receptors in various pathologies and to translate such information into the development of new intervention strategies. During the past funding period, we have made significant progress towards these goals. Specifically as described in the Progress Report, we have completed a series of studies to characterize the structure-function relationship and mechanism for binding and signaling of chemokine receptors, particularly CXCR4 that is one of two principal coreceptors required for the cellular entry of human immunodeficiency virus type 1 (HIV-1). Furthermore, we have developed a new strategy termed "Synthetically and Modularly Modified Chemokines (SMM-chemokines)" for structure-function analysis of ligand-receptor interactions and development of highly potent and specific receptor probes and therapeutic leads. Some of the SMM-chemokines specific for CXCR4 have been found to be highly promising candidates for developing new drugs to inhibit HIV-1 entry and infection. Building on this success in studying CXCR4 in HIV pathology and developing new anti-HIV drugs in the past funding period, here in this renewal application we propose to extend our research into a new area of stem cell biology and medicine involving chemokine receptors such as CXCR4 and its ligand SDF-1. Specifically, we will characterize the molecular mechanisms by which SDF-1 a and CXCR4 mediate stem cell-host interactions in the central nervous system (CNS) after injury, presumably as part of the process of stem cell engagement with a niche leading to subsequent efforts at repair. The underlying hypothesis is that chemokines and their receptors (particularly those involved in inflammatory cascades) actually play important roles in mediating the directed migration of human neural stem cells (hNSCs) to, as well as engagement and interaction with, sites of CNS injury, and that understanding and manipulating the molecular mechanism of chemokine- mediated stem cell homing and engagement will lead to new chemokine-mediated stem cell-based repair strategies for CNS injury.